Host Resistance Against Infections
Effective Routes for Enhancement of Host Resistance Against Infections
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
3 Approved without Funding
Institute of Highly Pure Biopreparations, Russia, St Petersburg
- Pharmascience, Inc., Canada, QC, Montreal\nUniversity of California, USA, CA, Los-Angeles\nUniversity of Minnesota / School of Public Health, USA, MN, St Paul\nUniversity of Notre Dame / Freimann Life Science Center, USA, IN, Notre Dame
Project summaryThe goal is to develop the effective method for man protection in case of bioterrorism through use of agents, which increase the colonization resistance (CR) of host mucosa.
A key problem facing the modern public health is protection of population from microbial and viral pathogens. Natural sources of highly dangerous infections are reliably controlled, but the probability of infecting is still high due to danger of bioterrorism. To protect population effectively, a variety of measures are necessary. Among these measures the enhancement of non-specific host resistance is of great importance as it provides a possibility of drawing almost the whole population in, is less laborious, less expensive and health enhancing. This subject has not received much attention yet. However, it has been known that well-balanced microflora of the internal body cavities exposed to the environment plays a crucial role in maintaining of colonization resistance.
In the modern view human microflora has been considered as a set of multiple microbiocenoses occupying numerous ecological sites on the skin and the mucous membranes of all body cavities, exposed to the environment. Total number of these bacterial cells in adult comes to 1014 cells, almost an order greater than the total cell number in host organs and tissues. Metabolic functions and interaction of microflora with the host probably affect human health and well being. Stimulants, inhibitors, hormones, vitamins, and other biologically active substances are involved in this metabolism. Inhibition of microflora may cause the onset of host metabolism disorders.
The well-balanced microflora of mucous membranes can be considered as an evolution-determined immunomodifier. The implication in production of the mucous colonization resistance to components of transitory microflora, which may contain different viral and bacterial pathogens, is the most important function of the resident microflora. The level of CR is of principal importance for prevention of host infections. It was demonstrated that the LD50 in conventional mice (with health microflora), contaminated by per os administration of bacterial suspension Salmonella enteritidis, was ~ 108 of cells, while in mice with disturbed microflora (experimentally-induced dysbacteriosis) it were the single cells that produced the same effect.
One of the main benefits of human microflora is protection from infections. But, every change in microbial equilibrium, i.e. modifications of microbial communities, caused either by antibiotics, by other drugs, or by stress, can carry negative consequences. In the middle 90th of XXth century multiple studies in microecology status of population in several European countries demonstrated that 90-97% of adults in Russia and Germany had microflora disorders. Judging from papers, after terrorism act in the USA on September 11, 2001 and the subsequent post letters with Anthrax, the emotional atmosphere undoubtedly affected the intestinal ecosystem of population. Besides, both events resulted in increased prophylactic administration of antibiotics. All these appeared to be a negative factor for normalizing of microflora and might evoke opportunistic infections. It should be noticed that antibiotics do not reduce the risk of infecting, caused by application of biological weapon, as strains stable to wide range of antibiotics are usually used for construction.
To enhance non-specific host resistance to pathogens, it is proposed to study the potential of probiotics and prebiotics, namely, of their different formulations, doses and routes for administration.
The scope of activities will include:
- Development of experimental animal model for control of CR. Development of methods for reduction of CR.
- Study of influence of probiotic Vitaflor (schedules, doses, formulations) on the level of CR in laboratory animals.
- Study of influence of prebiotic Actoflor (schedules, doses, formulations) on the level of CR in laboratory animals - for separate administration of Actoflor and for combined administration of both preparations.
- In vitro studies of mechanisms for Actoflor and Vitaflor activities towards infection agent.
- Recommendations for administration of these agents in volunteers.
Institute researchers have a great experience in creation of probiotics, in study of their properties and mechanisms for their activity. Vitaflor preparation has been produced at the institute. This agent contains viable microbial cells of two lactic acid strains, Lactobacillus acidophilus, specially selected by medical and biological characteristics. Symbiosis of the strains results in increase of biological potential of the preparation. Clinical trials demonstrated that Vitaflor normalized microflora of gut and other cavities, restored population of bifidobacteria and lactobacilli in the shortened terms; suppressed opportunistic bacteria, including Candida fungi; stimulated intestinal peristalsis; stimulated immunity, and decreased allergy. But to treat and prevent generalized infections specific formulations of the probiotic are needed, for example the sublingual one. Technologies for production of Vitaflor substance and of the ready-made formulations were developed and patented. Vitaflor is the only Russian well-characterized bacterial agent, which is produced in different formulations – powder, capsules, suppositories, sublingual tablets etc.
Study of mechanisms for probiotic activity revealed that besides specific antagonistic factors, such as bacteriocins, antibiotics, chelating agents, enzymes, and surfactants, the microorganisms produce a wide range of exometabolites, which prevent reproduction of pathogenic microorganisms and promote development of health microflora. Activity of these substances depends on qualitative and quantitative composition of microflora; on its sensitivity to own autoregulators and on ability to produce its own autoregulators. Deficiency of these substances may be covered by use of special agents. The first such agent Actoflor was developed at IHPB and is being currently tested at the institute. Combination of Actoflor with probiotics serves to increase activity of these agents. Actoflor may be also used independently for therapy and prophylaxis. Besides the improvement of gut microflora, Actoflor exerts strong health-improving effect, promotes growth of newborn animals, stimulates immunity, and in external administration promotes healing of wounds and ulcers.
The role of collaborators is to render assistance in research and in holding joint seminars. The project is in conformity with the goals and tasks of ISTC and is aimed at the development of effective route for man protection from bioterrorism. The results obtained for the project will contribute to solution of national and international problems related to bioterrorism control.